2,5 - dimethyl - 1,3,4,9b - tetrahydro-2h-indeno(1,2-c)pyridine and salts thereof

ABSTRACT

THE INVENTION CONCERNS 2,5-DIMETHYL-1,3,4,9B-TETRAHYDRO-2H-INDENO(1,2-C)PYRIDINE OF THE FORMULA:   2,5-DI(CH3-)-1,3,4,9B-TETRAHYDRO-2H-INDENO(1,2-C)PYRIDINE   AND ACID ADDITION SALTS THEREOF. PROCESSES FOR THE PRODUCTION OF THE ABOVE COMPOUNDS ARE ALSO DESCRIBED. THE COMPOUNDS ARE USEFUL SEDATIVE-NEUROLEPTICS, AND ALSO POSSESS USEFUL ANTIDEPRESSANT AND ANALGETIC PROPERTIES. ERTIES.

United States Patent 015cc 3,574,686 Patented Apr. 13, 1971 US. Cl.260-293 1 Claim ABSTRACT OF THE DISCLOSURE The invention concerns2,5-dimethy -l,3,4,9b-tetrahydro-2H-indeno[l,2-c]pyridine of theformula:

Jinan:

and acid addition salts thereof. Processes for the production of theabove compounds are also described.

The compounds are useful sedative-neuroleptics, and also possess usefulantidepressant and analgetic properties. erties.

The present invention concerns2,5-dimethyl-1,3,4,9btetrahydro-2H-indeno[1,2-c] pyridine of formula I,

(EH3 I and acid addition salts thereof.

The compound of Formula I and its salts may be produced by (a) removingwater from 2,5-dimethyl-5-hydroxy-1,2,3,

4,4a,9b-hexahydro-SH-indeno[1,2-c]pyridine of Formula II,

N-CHs OH: OH II 01 (b) treating1-phenyl1-(4-hydroxy-l-methylpiperidyl-4) ethan-l-ol of Formula III,

O H a i @ahc a...

(311; III

1 phenyl-1-(1-methyl-1,2,3,6-tetrahydropyridyl-4)ethan- 1-01 of FormulaIV,

or l-phenyl-l-(l methyl 1,2,3,6-tetrahydropyridyl-4) ethene of Formula Vwith a strong acid, and optionally reacting the resulting compound withan inorganic or organic acid.

Process (a) may, for example, be aifected as follows: The removal ofwater is alfected by treating 2,5-dimethyl- 5-hydroxy-l,2,3,4,4a,9bhexahydro 5H-indeno[1,2-c] pyridine, as free base or as acid additionsalt, with waterremoving agents at a temperature ranging from roomtemperature to the boiling temperature of the reaction mixture for about/2 to 24 hours. The reaction mixture is subsequently evaporated todryness and the resulting acid addition salt of the compound of FormulaI is optionally purified in manner known per se, e.g. by crystallizationfrom suitable solvents, e.g. lower alcohols such as isopropanol.

A strong acid is preferably used for the removal of water. Examples ofsuitable acids are mineral acids (eg in aqueous or alcoholic solution),such as hydrochloric, hydrobromic, hydriodic, sulphuric, phosphoricacid, or strong organic acids, e.g. organic sulphonic acids, such asmethanesulphonic, benzenesulphonic, napththalene-1,5-disulphonic acid.

An acid chloride of a strong acid, such as thionyl chloride ofmethanesulphonic acid chloride, or an acid anhydn'de, such as aceticanhydride, as well as other reagents suitable for the removal of Water,such as phophorus pentoxide, may likewise be used as water-removingagents. The compound of Formula II is conveniently heated to the boilunder reflux for about 10 to 45 minutes with a 4 to 6 N solution ofhydrogen chloride in a lower alkanol, e.g. ethanol, and the reactionmixture is subsequenlty evaporated to dryness; whereby 2,5-dimethyl-l,3,4,9b-tetrahydro-2H-indeno 1,2-c] pyridine hydrochloride isobtained as residue.

In accordance with process (b) the compound of Formula I is obtained bytreating a compound of Formulas III, IV, or V with a strong acid, e.g.with an aqueous solution of hydrogen bromide or an aqueous solution ofhydrochloric or sulphuric acid, or with methanesulphonic acid. Forexample, 1-phenyl-1-(1-methyl-l,2,3,6- tetrahydropyridyl-4)-ethan-1-olis added to an about 48% aqueous hydrogen bromide solution, the mixtureis subsequently stirred at a temperature of 2070 C. for about 2 hoursand is subsequently evaporated to dryness, Whereby2,5-dimethyl-l,3,4,9b-tetrahydro 2H indeno[1,2-c] pyridine hydrobromideis obtained as residue. The free base may be obtained by subsequenttreatment with an ammonium hydroxide solution.

2,5 dimethyl 1,3,4,9b-tetrahydro-2H-indeno[l,2-c] pyridine of Formula Imay be isolated and purified in manner known per se as free base or inthe form of one of its salts. It is a basic compound which forms stable,generally water-soluble and crystalline salts with inorganic and organicacids.

2,5 dimethyl 1,3,4-9b-tetrahydro-2H-indeno[1,2-c] pyridine, andpharmaceutically acceptable acid addition salts thereof, are usefulbecause they possess pharmacological activity in animals. In particular,the compounds are useful sedative-neuroleptic agents as indicated bytheir properties in potentiating barbiturate narcosis in mice, and ininhibiting amphetamine-induced locomotor activity, also in mice. Theneuroleptic activity of the compounds is also illustrated by theirproperties in inhibiting the socalled conditioned flight reaction (polejump experiment) in rats. The compounds also possess usefulantidepressant properties as indicated by the compounds eifects ininhibiting conditions of ptosis in rats produced by tetrabenazine.Furthermore, the compounds exhibit useful analgetic properties asindicated in the hot plate test and by their properties in inhibitingthe p-benzoquinone syndrome in mice, and the monkey tail test [Roemer,Proceedings of the International Symposium on Pain, Paris, April 1967,

3 in Pain, Academic Press, New York, London, 1968, pp. 165-l70].

For the abovementioned use, the dosage administered will of course varydepending upon the compound employed, mode of administration andtreatment desired. However, in general, satisfactory results areobtained for all indications at a daily dosage of from about 0.1milligram to about 10 milligrams per kilogram of animal body weight,preferably given in divided doses 2 to 3 times daily or in retard form.For the larger mammals, a suitable total daily dosage ranges from about10 to about 600 mg., and unit dosage forms suitable for oraladministration comprise from about 3 milligrams to about 300 milligramsof the particular compound admixed with a pharmaceutical carrier.

The new compounds may be used as medicaments on their own or in the formof appropriate medicinal preparations for enteral or parenteraladministration. In order to produce suitable medicinal preparations,which are also included in the present invention, the new compounds areworked up with inorganic or organic, pharmacologically inert adjuvants.Examples of such adjuvants are:

for tablets and drages: lactose, starch, talcum, stearic acid;

for capsules: tartaric acid, lactose;

for injectable solutions: water, alcohols, glycerin, vegetable oils;

for suppositories: natural or hardened oils, waxes.

The preparations may furthermore contain suitable preserving,stabilizing or wetting agents, solubilizers, sweetening or colouringsubstances and fiavourings.

Examples of suitable preparations are tablets or hard gelatin capsulescontaining 10 to 30 mg. of 2,5-dimethyll,3,4,9b tetrahydro-ZH-indeno1,2-c] pyridine hydrochloride.

Tablets may be produced by granulating, for example, about 6 parts of2,5-dimethyl-l,3,4,9b-tetrahydro-2H-indeno[1,2-c] pyridine hydrochloridewith about 12 parts of tartaric acid, about 2.5 parts of polyvinylpyrrolidone and about 2.5 parts of talc, about parts of maize starch,about 1 part of stearic acid and about 71 parts of lactose, and pressingthe resulting granulate into tablets.

Hard gelatin capsules are produced by mixing, for example, about 1 partof 2,5-dimethyl-1,3,4,9b-tetrahydro- 2H indeno[1,2-c]pyridinehydrochloride with about 2 parts of tartaric acid and about 36 parts oflactose, and filling the resulting mixture into capsules.

The starting materials for the production of 2,5-dimethyl l,3,4,9btetrahydro 2H indeno[l,2-c]pyridine may, for example, be obtained asfollows:

The compound II is obtained by reacting 2 methyl-5- oxo 1,2,3,4,4a,9bhexahydro 5H indeno[1,2-c]pyridine of Formula VI ll VI in an open-chainor cyclic ether, such as diethyl ether, with methyl lithium, andhydrolyzing the resulting reaction product, e.g. with an aqueousammonium chloride solution.

The compound of Formula IV is obtained by converting1-phenyl-1-(pyridyl-4)ethan-l-ol of Formula VII into the correspondingN-methyl-pyridinium compound, e.g. by reacting with methyl bromide ormethyl iodide, and reducing the N-methyl-pyridinium compound to thecompound of Formula IV. This reduction is preferably effected withsodium borohydride in a solvent which is inert under the reactionconditions, e.g. methanol or another alkanol, optionally mixed withwater.

The compound III is obtained by brominating4-benzoyl-l-methyl-piperidine in the 4 position, e.g. by reacting thehydrobromide with bromine in glacial acetic acid, reacting the resulting4-benzoyl-4-bromo-l-methyl-piperidine with an alkali metal alcoholate,treating the reaction product with an acid, converting the resulting4-benzoyl-4- hydroxy-l-methyl-piperidine into l-phenyl-l-(4-hydroxy-1methylpiperidyl-4)ethan-l-ol by reaction with a methyl magnesium halidein an open-chain or cyclic ether, and then hydrolyzing the resultingreaction product.

The compound of Formula V is produced by removing water from 1phenyl-l-(lmethyl-l,2,3,6-tetrahydropyridyl-4)ethan-l-ol. This removalof water may be effected by heating with an acid. Acids which may beused are inorganic acids, e.g. hydrochloric acid, and organic acids. Thereaction may likewise be effected in a solvent which is inert under thereaction conditions. The resulting compound of Formula V may optionallybe converted into its acid addition salts by treating with inorganic ororganic acids.

In the following non-limitative examples all temperatures are indicatedin degrees centigrade and are uncorrected.

EXAMPLE 1 2,5-dimethyl-1,3 ,4,9b-tetrahydro-2H-indeno[1,2c] pyridine Asolution of 14 g. of 2.5-dimethyl-5-hydroxy-1,2,3,4,4a,9b-hexahydro-5H-indeno[1,2-c]pyridine in 200 cc. of a 5 N solution ofhydrogen chloride in ethanol is heated to the boil at reflux for 15minutes. The solution is subsequently evaporated to dryness. Afterrecry'stallizing the residue twice from isopropanol pure2,5-dimethyl-1,3,4,9btetrahydro-2H-indeno[l,2-c]pyridine hydrochloridehaving a M.P. of 203-205 (decomp) is obtained.

The 2,5 dimethyl 5hydroxy-1,2,3,4,4a,9b-hexahydro-5H-indeno[l,2-c]pyridine, used asstarting material, may be produced as follows:

100 cc. of a 4.4% solution of methyl lithium in ether is added dropwiseat 30 while stirring to a suspension of 32.2 g. ofZ-methyl-S-oxo-1,2,3,4,4a,9b-hexahydro-5H-indeno[l,2-c] pyridine in 300cc. of absolute ether. After the addition is completed the reactionmixture is stirred at 20 for 3 hours, cc. of a 20% ammonium chloridesolution are added dropwise while cooling with ice and in an atmosphereof nitrogen, and extraction is effected with ether. The combined etherextracts are dried over magnesium sulphate, the magnesium sulphate isremoved by filtration and the filtrate is evaporated to dryness. Theresidue, a crystalline crude product, is recrystallized twice fromdiisopropyl ether, whereby pure2,5-dimethyl-5-hydroxy-1,2,3,4,4a,9bhexahydro-SH-indeno l,2-c]-pyridine,having a M.P. of 132-134, is obtained.

EXAMPLE 2 2,5-dimethyl-1,3 ,4,9b-tetrahydro-2H-indeno 1,2-c] pyridine2,3 g. of l-phenyl1-(l-methyl-1,2,3,6-tetrahydropyridyl-4)ethan-1-ol areadded portionwise while stirring to 30 cc. of a 48% aqueous solution ofhydrogen bromide. The mixture is stirred at room temperature for 2 hoursand is subsequently evaporated to dryness at 60 under reduced pressure.The residue is taken up in a 2 N ammonium hydroxide solution, theliberated base is extracted with benzene and the extracts are dried overmagnesium sulphate; the solvent is evaporated and the residue isdistilled in a vacuum, whereby2,5-dimethyl-1,3,4,9btetrahydro-2H-indeno[1,2-c]pyridine distills overat (temperature measured in the air bath). The hydrochloride has a M.P.of 203-205 (decomp) after crystallization from isopropanol.

The l-phenyl-l-(l-methyl 1,2,3,6 tetrahydropyridyl- 4)-ethan-1-o1, usedas starting material, may be produced as follows:

45 g. of gaseous methyl bromide are passed through a solution of 9.6 g.of l-phenyl-l-(pyridyl-4)ethan-1-ol in 100 cc. of methanol at atemperature of 10 to while stirring. The reaction mixture is stirred atroom temperature overnight and is subsequently evaporated to dryness.The resulting residue is taken up in 350 cc. of methanol and 18.4 g. ofsodium borohydride are added portionwise while stirring, whereby thetemperature is maintained between 20 and 30 by cooling occasionallly.The reaction mixture is stirred at room temperature for 17 hours, issubsequently concentrated by evaparotion at 50 and reduced pressure, theresidue is taken up in 100 cc. of water and is extracted several timeswith chloroform. The organic phases are combined, dried over magnesiumsulphate and concentrated by evaporation, whereby 1 phenyl 1(l-methyl-1,2,3,6-tetrahydropyridyl- 4)ethan-l-ol is obtained asresidue; M.P. 138-140 after crystallization from benzene.

EXAMPLE 3 2,5-dimethyl-1,3,4,9b-tetrahydro-2H-indeno 1,2-c] pyridine Asolution of 50 g. of 1-phenyl-1-(1-methyl-1,2,3,6-tetrahydropyridyl-4)ethan-l-ol in 500 cc. of 20% hydrochloric acid isheated to the boil for 15 hours. The reaction mixture is concentrated byevaporation at 60 and reduced pressure, the residue is taken up in waterand potassium carbonate is added to the solution until a strong alkalinereaction is obtained (pH about The liberated base is extracted withether, the combined etheral extracts are dried over magnesium sulphateand the solvent is evaporated. The residue is distilled in a bulb tubeunder reduced pressure, B.P. l30-140/0.2 mm. of Hg. (temperaturemeasured in the air bath). The distillate is dissolved in 30 cc. ofisopropanol and the calculated amount of hydrochloric acid in ethanol isadded, whereup after cooling to 0 pure2,5-dimethyl-1,3,4,9b-tetrahydro-2H- indeno[1,2-c]pyridinehydrochloride, having a M.P. of 197-200 (decomp.), crystallizes.

tetrahydropyridyl -4)ethene in 300 cc. of 47% hydrobromic acid isallowed to react at room temperature for 6 3 hours. The reaction mixtureis worked up as described in Example 3, whereby2,5-dimethyl-l,3,4,9b-tetrahydr0- 2H-indeno[l,2-c]pyridinehydrochloride, having a M.P. of 20l-203 (decomp.), is obtained.

The 1-phenyl-1-( l-methyl- 1,2,3 ,6-tetrahydropyridyl-4 ethene, used asstarting material, may be produced as follows:

A solution of 54.2 g. of l-phenyl-l(1methyl-1,2,3,6-tetrahydropyridyl-4)ethan-l-ol in 300 cc. of 2 N hydrochloric acid isheated to 100 for 1 hour. The reaction mixture is evaporated to drynessunder reduced pressure, the residue is taken up in water, and potassiumcarbonate is added to the solution until a strong alkaline reaction isobtained (pH about 10). After extracting the liberated base with etherand drying the combined ethereal extracts over magnesium sulphate, thesolvent is evaporated. The residue is distilled under reduced pressure,whereby pure 1 phenyl-1-(l-methyl-l,2,3,6-tetrahydropyridyl-4) ethene,having a B.P. of 103-105 0.008 mm. of Hg is obtained.

The base is converted into the hydrogen meleate by adding a saturatedethereal solution of the calculated amount of maleic acid to an etherealsolution of the base, whereby crystallization sets in spontaneously.After crystalling the resulting product from acetone/ ether l-phenyl- 1(l methyl 1,2,3,6 tetrahydropyridyl-4) ethene hydrogen maleate, having aM.P. of 96.5, is obtained.

What is claimed is:

1. 2,5 dimethyl 1,3,4,9b tetrahydro 2H-indeno [1,2-c]pyridine of theformula:

and pharmaceutically acceptable acid addition salts thereof.

References Cited Fox et 211.: J. Org. Chem. 16, 1259-61 (1951).

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner U.S. Cl.X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,571+,686 Dated April 13, 1971 nv nt Ernst Jucker. Anton Ebnother andJean-Michel Bast:

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1 line 28 delete the letters "erties".

Column 1 structure I should be as follows Column 2 line 23 delete theword "of" and insert or Signed and sealed this 9th day of April 1971+.

(SEAL) Attest:

EDWARD M .FLETCHER,JR. C. MARSHALL DANN Attes ting Officer Commissionerof Patents

